Self-assembly Process Research Articles

Redox-active polyoxovanadates as cofactors in the development of functional protein assemblies

The interactions of polyoxovanadates (POVs) with proteins have increasingly attracted interest in recent years due to their potential biomedical applications. This is especially the case because of their redox and catalytic properties, which make them interesting for developing artificial metalloenzymes. Organic-inorganic hybrid hexavanadates in particular offer several advantages over all-inorganic POVs. However, they have been scarcely investigated in biological systems even though, as shown in this work, hybrid hexavanadates are highly stable in aqueous solutions up to relatively high pH. Therefore, a novel bis-biotinylated hexavanadate was synthesized and shown to selectively interact with two biotin-binding proteins, avidin and streptavidin. Bridging interactions between multiple proteins led to their self-assembly into supramolecular bio-inorganic hybrid systems that have potential as artificial enzymes with the hexavanadate core as a redox-active cofactor. Moreover, the structure and charge of the hexavanadate core were determined to enhance the binding affinity and slightly alter the secondary structure of the proteins, which affected the size and speed of formation of the assemblies. Hence, tuning the polyoxometalate (POM) core of hybrid POMs (HPOMs) with protein-binding ligands has been demonstrated to be a potential strategy for controlling the self-assembly process while also enabling the formation of novel POM-based biomaterials that could be of interest in biomedicine.

Self-assembled Sm0.5Sr0.5CoO3-δ-Ce0.8Sm0.2O2-δ composite for solid oxide electrolysis cells

The anode is the key material that constrains the performance of solid oxide electrolysis cells (SOECs). Here, we have developed self-assembled Sm0.5Sr0.5CoO3-δ-Ce0.8Sm0.2O2-δ (SSC-SDC) composite by the co-synthesis strategy and studied its electrochemical performance as the anode for SOECs. The surface and interface properties of the self-assembled SSC-SDC composite were systematically studied. The SDC lattice expansion and the SSC lattice contraction of the SSC-SDC composite have been shown by XRD analysis, ascribed to the strong cation interdiffusion during the self-assembly process. The self-assembled SSC-SDC also exhibits superior oxygen evolution activity and displays a larger oxygen desorption peak than the physically mixed SSC&SDC. A higher proportion of adsorbed oxygen species on the surface of the self-assembled SSC-SDC than the physically mixed SSC&SDC also have been shown by XPS results. The cell with the self-assembled SSC-SDC as anode exhibits ca. 2.1 times higher current density than the physically mixed SSC&SDC as anode. Meanwhile, the polarization resistance of the cell with self-assembled SSC-SDC as the anode is 0.0957 Ω cm2, which is only 40 % of that observed in the cell where SSC and SDC are physically mixed as the anode. This novel self-assembly strategy shows great potential for preparing high-performance oxygen electrodes.

A multi-stimuli-responsive fluorescence material based on 1,8-naphthalimide.

A pair of 1,8-naphthalimides (NPIs) were designed and successfully synthesized through embellishing amino-containing NPI with 4-diethylaminosalicyladehyde and 4-diethylaminobenzaldehyde, respectively. Their structures were fully confirmed by 1H/13C NMR, HR-MS and FT-IR spectroscopic studies. Their photophysical properties were systematically investigated in different solvents of varied polarity, in THF/water mixtures with varying water fractions (fw), and in THF solvent with varying concentrations of NPIs. It inferred that the distinct differences in emission between two NPIs during self-assembled process could be ascribed that the hydroxyl-containing NPI allowed the excited-state intramolecular proton transfer process between -OH and CH=N units in the aggregation state. Interestingly, the solid of 4-diethylaminosalicyladehyde-functionalized NPI exhibited multi-stimuli-responsive fluorescence changes involving mechanofluorochromism and HCl/NH3 vapor stimulus-induced conversion. However, no remarkable change was observed in the photoluminescence (PL) spectra for the solid of 4-diethylaminobenzaldehyde-functionalized NPI under the stimuli of mechanical force and organic solvent.

A biomimetic branching signal-passing tile assembly model with dynamic growth and disassembly.

Natural biological branching processes can form tree-like structures at all scales and, moreover, can perform various functions to achieve specific goals; these include receiving stimuli, performing two-way communication along their branches, and dynamically reforming (extending or retracting branches). They underlie many biological systems with considerable diversity, frequency, and geometric complexity; these include networks of neurons, organ tissue, mycorrhizal fungal networks, plant growth, foraging networks, etc. This paper presents a biomimetic DNA tile assembly model (Y-STAM) to implement dynamic branching processes. The Y-STAM is a relatively compact mathematical model providing a design space where complex, biomimetic branch-like growth and behaviour can emerge from the appropriate parametrization of the model. We also introduce a class of augmented models (Y-STAM+) that provide time- and space-dependent modulations of tile glue strengths, which enable further diverse behaviours that are not possible in the Y-STAM; these additional behaviours include refinement of network assemblies, obstacle avoidance, and programmable growth patterns. We perform and discuss extensive simulations of the Y-STAM and the Y-STAM+. We envision that these models could be applied at the mesoscale and the molecular scale to dynamically assemble branching DNA nanostructures and offer insights into complex biological self-assembly processes.

Developing Supramolecular Metallogel Derived from Pd2L4 Cage Molecule for Delivering an Anti-Cancer Drug to Melanoma Cell B16-F10.

Supramolecular gels are an important class of materials that are promising for its wide range of applications including drug delivery. While supramolecular gels are intrinsically porous because of the 3D nano-matrix (gel matrix) that is being formed due to supramolecular self-assembly process involving the gelator molecules during gelation, additional nanopores can be introduced to the overall gel if the gelator molecule itself holds molecular cavity such as metal-organic-cage (MOC) molecules. A MOC having the molecular formula [(Pd2L24).4NO3].3H2O.2DMF.MeOH (Pd-cage) (L2=5-Azido-N,N'-di-pyridin-3-yl-isophthalamide) was successfully synthesized and characterized by FT-IR, 1H NMR, ESI-MS and single crystal X-ray diffraction. Stimuli-reversible supramolecular metallogel PdG could easily be formed from Pd-cage in DMSO/water mixture. The molecular cage of Pd-cage was demonstrated to be available for loading an anti-cancer drug namely doxorubicin (DOX). Subsequently, DOX was also loaded within PdG and delivered to melanoma cell line B16-F10 displaying significant anti-cancer activity as revealed by both MTT and scratch assay. Rheoreversibility of PdG and its ability to load and deliver DOX to cancer cells clearly raised hope for developing this metallogel further as topical anticancer gel.

Fluorescent Nanocable as a Biomedical Tool: Intracellular Self-Assembly Formed by a Natural Product Interconnects and Synchronizes Mitochondria.

Self-assembly processes commonly occur in various biological contexts to form functional biological structures. However, the self-assembly of nanofibers within cells by heterologous molecules showing a biological function is rare. In this work, we reported the intracellular formation of fluorescent nanofibers by a natural small molecule, lycobetaine (LBT), which facilitated the direct physical connection between mitochondria and synchronized their membrane potential oscillations. The luminescent properties of LBT enabled the real-time observation of nanofiber formation, while the semiconductive nature of the LBT nanofiber facilitated electrical signal transduction among the connected mitochondria. This study introduces an approach to modulate mitochondrial connectivity within cells using "nano-cables" which facilitate studies on synchronized mitochondrial operations and the underlying mechanisms of drug action.

A Schottky/Z-Scheme Hybrid for Augmented Photocatalytic H2 and H2O2 Production.

The prodigious employment of fossil fuels to conquer the global energy demand is becoming a dreadful threat to the human society. This predicament is appealing for a potent photocatalyst that can generate alternate energy sources via solar to chemical energy conversion. With this interest, we have fabricated a ternary heterostructure of Ti3C2 nanosheet modified g-C3N4/Bi2O3 (MCNRBO) Z-scheme photocatalyst through self-assembly process. The morphological analysis clearly evidenced the close interfacial interaction between g-C3N4 nanorod, Bi2O3 and Ti3C2 nanosheets. The oxygen vacancy created on Bi2O3 surface, as suggested by XPS and EPR analysis, supported the Z-scheme heterojunction formation between g-C3N4 nanorod and Bi2O3 nanosheets. The collaborative effect of Z-scheme and Schottky junction significantly reduced charge transfer resistance promoting separation efficiency of excitons as indicated from PL and EIS analysis. The potential of MCNRBO towards photocatalytic application was investigated by H2O2 and H2 evolution reaction. A superior photocatalytic H2O2 and H2 production rate for MCNRBO is observed, which are respectively around 5 and 18 folds higher as compared to pristine CNR nanorod. The present work encourages for the development of a noble, eco-benign and immensely efficient dual heterojunction based photocatalyst, which can acts as saviour of human society from energy crisis.

Poly(l-proline)-Stabilized Polypeptide Nanostructures via Ring-Opening Polymerization-Induced Self-Assembly (ROPISA).

Poly(proline) II helical motifs located at the protein-water interface stabilize the three-dimensional structures of natural proteins. Reported here is the first example of synthetic biomimetic poly(proline)-stabilized polypeptide nanostructures obtained by a straightforward ring-opening polymerization-induced self-assembly (ROPISA) process through consecutive N-carboxyanhydride (NCA) polymerization. It was found that the use of multifunctional 8-arm initiators is critical for the formation of nanoparticles. Worm-like micelles as well as spherical morphologies were obtained as confirmed by dynamic light scattering (DLS), transmission electron microscopy (TEM), and small angle X-ray scattering (SAXS). The loading of the nanostructures with dyes is demonstrated. This fast and open-vessel procedure gives access to amino acids-based nanomaterials with potential for applications in nanomedicine.

Concentration modulated microstructure and rheological properties of nanofibrous hydrogels derived from decellularized human amniotic membrane for 3D cell culture

Decellularized amnion (dAM)-derived hydrogels have been extensively exploited for versatile medical and therapeutical applications, particularly for soft tissue engineering of skin, vascular graft, and endometrium. In contrast to polyacrylamide-based hydrogels, which have been extensively employed as a 3D cell culture platform, the cell response of dAM hydrogel is yet to be understood. In this study, we have prepared hydrogels containing different concentrations of dAM and systematically investigated their microstructural features, gelation kinetics, and rheological properties. The results show that dAM hydrogels possess a network of fibers with an average diameter of 56 ± 5 nm at 1% dAM, which increases to 110 ± 14 nm at 3% dAM. The enhanced intermolecular crosslinking between the microfibrillar units increases the gelation rate in the growth phase of the self-assembly process. Moreover, increasing the concentration of dAM in the hydrogel formulation (from 1 to 3%w/v) enhances the dynamic mechanical moduli of the derived hydrogels by about two orders of magnitude (from 41.8 ± 2.5 to 896.2 ± 72.3 Pa). It is shown that the variation in the hydrogel stiffness significantly affects the morphology of dermal fibroblast cells cultured in the hydrogels. It is shown that the hydrogels containing up to 2%w/v dAM provide a suitable microenvironment for embedded fibroblast cells with spindle-like morphology. Nevertheless, at the higher concentration, an adverse effect on the proliferation and morphology of fibroblast cells is noticed due to stiffness-induced phenotype transformation of cells. Concentration-modulated properties of dAM hydrogels offer an in vitro platform to study cell-related responses, disease modeling, and drug studies.Graphical abstract

Dimerization and liquid-liquid phase separation of the nonrepetitive domains of pyriform spidroin 1 controls the pyriform silk formation

Spiders spin high performance silks with diverse mechanical properties for specific biological functions. Of these spider silk types, pyriform silk stands out as a unique combination of wet glue and dry fibers. Investigation of self-assembly process of spider silk proteins is necessary for elucidating the silk formation mechanism. However, the functions of nonrepetitive domains in the silk formation of pyriform spidroins from liquid proteins to solid fibers are still unclear, making it difficult to achieve efficient biomimetic preparations of pyriform silk with good mechanical properties. In this study, we investigate the roles of the N-linker repeat (NLR) and both terminal domains of pyriform spidroin 1 (PySp1) in the silk formation. We demonstrate for the first time that the PySp1 NLR alone is sufficient to self-assemble into high strength fibers. Moreover, we showed that the ability to promote the pyriform silk formation by the addition of the NLR. We also found that the pH-sensitive dimerization property for N-terminal domain and the liquid-liquid phase separation (LLPS) coupled with acidification triggers the self-assembly mediated by the C-terminal domain. Overall, our results provide new insight into the role of nonrepetitive domains in the pyriform silk formation mechanism and the basis for producing new protein-based materials derived from spider pyriform silk.

A molecular synergy of non-covalent interactions facilitated via theobromine modifying the self-assembly process of type I collagen

Type I Collagen is a multifunctional fibrous protein present significantly in the connective tissues. Generally, fibril formation process of an interstitial collagen begins with a triple helix alignment to form a pentafibril, which sequentially self-assembles into a microfibril. Typically, this sequential formation can be achieved under an in vitro condition as well by maintaining certain specific physiological parameters to mimic the interstitial microenvironment of collagen. The necessity to study such a kinetically driven process is due to its implications in template fabrication particularly as a scaffold to enhance the growth of specific stem cells or accelerating nanoparticle synthesis. Drawing inspiration from this, theobromine, a methylxanthine that contributes towards the hydrogen bond network via dimerization and stacking interaction was used as a small molecule in modifying the molecular level interactions of a self-assembled collagen. Initially, rheological studies revealed certain variations in the viscous properties of collagen on addition of theobromine. Turbidity assay showed an increase in the rate of fibril formation and its topographical changes were observed through the high-resolution scanning electron microscope. The stability and probable physico-chemical interactions between collagen and theobromine were comprehended from the vibrational frequency changes recorded using (FT-IR) (ATR) and conformational changes using Circular Dichroism (CD) studies. Our results show possible multibinding sites on theobromine, which would compete to bind with the polar and non-polar residues exposed over the monomeric surfaces of triple helix causing a local conformational fluctuation modifying protein-protein interaction.

3D porous PEDOT/MXene scaffold toward high-performance supercapacitors

3D architectures of conductive polymer, especially PEDOT hold great promise in energy storage and conversion fields. However, the facile construction of 3D PEDOT and its functionalization have still been challenges due to its poor processability. Herein, the fabrication of 3D porous PEDOT:PSS and its functionalization with MXene are realized synchronously through a simple and low-cost self-assembly process. The prominent capacitive performance of MXene, excellent chemical stability of PEDOT:PSS and 3D porous architecture with inhibited aggregation of MXene nanosheets, large amount of active sites, and electrolyte storage chamber endow the PEDOT/MXene-based porous structure with superior capacitive performance than individual PEDOT:PSS or MXene porous and flat structures. Furthermore, the PEDOT/MXene-based porous structure can be applied as a flexible scaffold for the deposition of conductive polymer to construct excellent electrodes for supercapacitors (SCs). When polypyrrole (PPy) is deposited, the prepared porous PEDOT:PSS/MXene/PPy electrode exhibits a high gravimetric specific capacitance of 345 F g−1 at a current density of 0.5 A g−1 and a remarkable capacitance retention of 89 % over 5000 cycles. Based on it, an asymmetric supercapacitor (ASC) with a high energy density of 56.34 Wh kg−1 at the power density of 120 W kg−1, and a capacitance retention of 75 % after 5000 cycles is developed. Besides, the porous PEDOT:PSS/MXene/PPy can be constructed on various substrates in any pattern with high design freedom, thus enabling customizable electrochemical performance. When constructing on a flexible substrate, excellent deformation-tolerant performance is shown. This work provides a high-performance electrode for SCs, as well as a universal route for the construction and functionalization of 3D PEDOT-based structures.

Robust self-assembly of nonconvex shapes in two dimensions.

We present fast simulation methods for the self-assembly of complex shapes in two dimensions. The shapes are modeled via a general boundary curve and interact via a standard volume term promoting overlap and an interpenetration penalty. To efficiently realize the Gibbs measure on the space of possible configurations we employ the hybrid Monte Carlo algorithm together with a careful use of signed distance functions for energy evaluation. Motivated by the self-assembly of identical coat proteins of the tobacco mosaic virus which assemble into a helical shell, we design a nonconvex two-dimensional model shape and demonstrate its robust self-assembly into a unique final state. Our numerical experiments reveal certain essential prerequisites for this self-assembly process: blocking and matching (i.e., local repulsion and attraction) of different parts of the boundary, and nonconvexity and handedness of the shape.

Adoption of a Tetrahedral DNA Nanostructure as a Multifunctional Biomaterial for Drug Delivery.

DNA nanostructures have been widely researched in recent years as emerging biomedical materials for drug delivery, biosensing, and cancer therapy, in addition to their hereditary function. Multiple precisely designed single-strand DNAs can be fabricated into complex, three-dimensional DNA nanostructures through a simple self-assembly process. Among all of the synthetic DNA nanostructures, tetrahedral DNA nanostructures (TDNs) stand out as the most promising biomedical nanomaterial. TDNs possess the merits of structural stability, cell membrane permeability, and natural biocompatibility due to their compact structures and DNA origin. In addition to their inherent advantages, TDNs were shown to have great potential in delivering therapeutic agents through multiple functional modifications. As a multifunctional material, TDNs have enabled innovative pharmaceutical applications, including antimicrobial therapy, anticancer treatment, immune modulation, and cartilage regeneration. Given the rapid development of TDNs in the biomedical field, it is critical to understand how to successfully produce and fine-tune the properties of TDNs for specific therapeutic needs and clinical translation. This article provides insights into the synthesis and functionalization of TDNs and summarizes the approaches for TDN-based therapeutics delivery as well as their broad applications in the field of pharmaceutics and nanomedicine, challenges, and future directions.

Encapsulation and controlled delivery of curcumin by self-assembled cyclodextrin succinate/chitosan nanoparticles

Low aqueous dispersibility and poor stability severely restrict the bioaccessibility of curcumin in health-related products. Constructing highly effective delivery carriers is essential to overcome the limitation. In this study, a novel and simple self-assembly process driven by electrostatic interaction was developed to prepare cyclodextrin succinate/chitosan (SACD/CS) nanoparticles. Spherical SACD/CS nanoparticles were obtained by adjusting the ratio of SACD:CS to obtain an average size and ζ-potential of around 500 nm and 20 mV, respectively. By analyzing the intermolecular interactions and crystalline structure of SACD/CS nanoparticles, it is indicated that SACD could act as crosslinking nodes, and contributed to transformation of molecular arrangement in the nanoparticles. The noncytotoxic SACD/CS nanoparticles were further used as curcumin carriers and showed significant improvement on curcumin stability, with the retention index of curcumin under physiological conditions increased from 19% to 62%. Moreover, the Cur-SACD/CS nanoparticles displayed controlled release behavior of curcumin during in vitro digestion, with 9%, 22%, and 44% of curcumin released at the end of the oral, stomach, and small intestine stage, respectively. This study developed a novel and effective strategy for oral delivery of curcumin, showing promising potential for improving the bioaccessibility and bioavailability of bioactive compounds like curcumin.

Spherulite formation in green nonaqueous media: The impact of urea on gelation in glycerol

HypothesisLarge macroscopic assemblies formed by a surfactant, sodium dodecylsulfate (SDS), and glycerol, can be directed to assemble in a hierarchical manner by the addition of a strong hydrogen-bond donor/acceptor, such as urea. ContextSelf-assembly in complex media is important to a range of applications, for instance in biological media, which are multi-component, to industrial formulations, where additives are present for flavour, texture, and preservation. Here, the gelation and self-assembly of sodium dodecylsulfate (SDS) in glycerol is explored in the presence of an additive, urea. Urea was chosen due to its importance both fundamentally and industrially, but also because of its ability to form strong H-bonds and interact with both glycerol and SDS. ExperimentalTo cover the variety of length scales present in the gel-like phase, a combination of optical microscopy and small-angle X-ray scattering techniques were used to probe the micro- to nanoscale. FindingsOn the microscale, the formation of a spectacular spherulite phase, even at low urea contents - 0.1 wt%, upon cooling was observed, a stark difference to the microfibrillar phase observed in the absence of urea. Interestingly, the nanostructure of the two crystalline phases were similar and showed negligible differences. This suggests that urea is not involved in the SDS/glycerol microfibril formation but instead directs the assembly of spherulites by bundling the microfibrils. These ternary systems are also probed as a function of urea content, SDS concentration, and temperature. The observations in this work highlight the importance of small molecules in the self-assembly process, which is relevant both fundamentally but also industrially, where small molecules are often added to formulations.

Poly(Photosensitizer-Prodrug) Unimolecular Micelles for Chemo-Photodynamic Synergistic Therapy of Antitumor and Antibacteria.

It is crucial to use simple methods to prepare stable polymeric micelles with multiple functions for cancer treatment. Herein, via a "bottom-up" strategy, we reported the fabrication of β-CD-(PEOSMA-PCPTMA-PPEGMA)21 (βPECP) unimolecular micelles that could simultaneously treat tumors and bacteria with chemotherapy and photodynamic therapy (PDT). The unimolecular micelles consisted of a 21-arm β-cyclodextrin (β-CD) core as a macromolecular initiator, photosensitizer eosin Y (EOS-Y) monomer EOSMA, anticancer drug camptothecin (CPT) monomer, and a hydrophilic shell PEGMA. Camptothecin monomer (CPTMA) could achieve controlled release of the CPT due to the presence of responsively broken disulfide bonds. PEGMA enhanced the biocompatibility of micelles as a hydrophilic shell. Two βPECP with different lengths were synthesized by modulating reaction conditions and the proportion of monomers, which both were self-assembled to unimolecular micelles in water. βPECP unimolecular micelles with higher EOS-Y/CPT content exhibited more excellent 1O2 production, in vitro drug release efficiency, higher cytotoxicity, and superior antibacterial activity. Also, we carried out simulations of the self-assembly and CPT release process of micelles, which agreed with the experiments. This nanosystem, which combines antimicrobial and antitumor functions, provides new ideas for bacteria-mediated tumor clinical chemoresistance.

Incorporation strategy for organic dyes into gold nanoparticle supercrystals.

Ordered arrays of plasmonic nanoparticles, supercrystals can lead to the formation of plasmon-polaritons. Coupling light emitters with plasmon polaritons might allow the formation of exciton-plasmon polaritons with properties tuneable by the supercrystal design. To construct such optically active materials, the inclusion of emitters is imperative. The addition of organic dyes without affecting the periodic order of the nanocrystals is difficult, as post-formation protocols might dissolve the supercrystals, and pre-formation addition might affect the self-assembly process. Here, we present an exemplary strategy to functionalize gold nanoparticles prior to self-assembly with a cyanine isothiocyanate dye that was obtained by a straightforward reaction of the amine functionalized dye with carbon disulfide. In the second step, the nanoparticles are functionalized with a thiol-terminated polystyrene, which stabilizes the nanoparticles and governs the self-assembly process. The dye can be integrated in a quantitative fashion, and the nanoparticles can be self-assembled into supercrystals. The strategy should be applicable in general for amine functionalized dyes, which is a common modification.

Assembly of polysaccharide-based polymer brush for supramolecular hydrogel dressing

Extracted from Platycodon grandiflorum, platycodon grandiflorum polysaccharides (PGPs) with diverse biological functions have been extensively employed for modification and fabrication of hydrogels for biomedical applications, such as wound dressings. However, since the lack of effective structural design, the reported polysaccharide-based hydrogel dressings are still suffered from structural failures and limited bio-functionality. Herein, we demonstrate a facile and general strategy to fabricate a supramolecular hydrogel composed of PGP-based polymer brush as building blocks combined with a Ca2+-mediated self-assembly process. The specific polymer brush with high branch functionality was achieved with polyacrylamide arms evenly grown on the PGP (grafting efficiency as high as 80 %) with series of chemical modifications. With above structural merits, the resulting hydrogel with densely crosslinked polymer brush featured enhanced mechanical strength as well as self-healing, and shear-thinning behaviors. Further biocompatible investigation indicated the as-prepared hydrogels with admirable performances in self-adhesion (adhesive strength of 16.7–79.5 kPa), a pH-responsive swelling ratio as high as 44 at pH 5.4, and pH-responsive degradation. They also showed antioxidant capacity by scavenging DPPH activity of nearly 80 % in 20 min, hemocompatibility, cell viability and cell migration. Impressively, the PGP-based polymer brush hydrogel served as a wound dressing revealed significant acceleration on wound closure.

Directed Self-Assembly by Sparsely Prepatterned Substrates with Self-Responsive Polymer Brushes.

The guiding pattern in the chemoepitaxially directed self-assembly (DSA) of block copolymers is often fabricated by periodically functionalizing homogeneously random copolymer brushes tethered on a substrate. The prepatterned copolymer brushes constitute a soft penetrable surface, and their two components can in principle locally segregate in response to the overlying self-assembly process of block copolymers. To reveal how the self-responsive behavior of the copolymer brushes affects the directing effect, we develop a dissipative particle dynamics model to explicitly include the prepatterned polymer brushes and implement it to simulate the DSA of a cylinder-forming diblock copolymer melt on the sparse pattern of polymer brushes. Through large-scale dynamic simulations, we identify the windows of the content of the random copolymer, the film thickness, and the diameter of the patterned spot, for the formation of perfectly ordered hexagonal patterns composed of perpendicular cylinders. Our dynamic simulations reveal that the random copolymer brushes grafted on the unpatterned area exhibit a remarkable self-responsive ability with respect to the self-assembly of the diblock copolymers overlying them, which may widen the effective window of the content of the random copolymer. Within the processing windows of these key parameters, defect-free patterns are successfully achieved both in simulations and in experiments with sizes as large as a few micrometers for 4-fold density multiplications. This work demonstrates that highly efficient computer simulations based on an effective model can provide helpful guidance for experiments to optimize the critical parameters and even may promote the application of DSA.